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991.
992.
Lalloo AK McConnell EL Jin L Elkes R Seiler C Wu Y 《International journal of pharmaceutics》2012,431(1-2):90-100
Gastric retention is postulated as an approach to improve bioavailability of compounds with narrow absorption windows. To elucidate the role of image size on gastric retention and pharmacokinetics, formulations with different image sizes and swelling kinetics but similar dissolution rates were designed and imaged in dogs. Diet had a clear effect, with increasing calorific intake prolonging retention in the dog model. In contrast to clinical observations, no obvious effect of image size on gastric retention was observed in the dog, with the larger gastric retentive (GR) and smaller controlled release (CR) formulations both demonstrating similar gastric emptying. Comparable pharmacokinetic profiles were observed for the two formulations, corroborating the imaging data and providing evidence of similar in vivo dissolution rates and dosage form integrity in the dog. Food, specifically meal composition, resulted in comparable enhancements in exposure in the dog and clinic due to prolonged gastric retention. However, differentiating retention based on image size in the dog was not feasible due to the smaller pyloric aperture compared to humans. This work illustrates that the dog is capable of determining the pharmacokinetic advantage of gastric retention relative to immediate release (IR) or CR formulations, however, has limited value in differentiating between CR and GR formulations. 相似文献
993.
Dobrovolsky VN Elespuru RK Bigger CA Robison TW Heflich RH 《Environmental and molecular mutagenesis》2011,52(9):784-794
The endogenous X-linked PIG-A gene is involved in the synthesis of glycosyl phosphatidyl inositol (GPI) anchors that tether specific protein markers to the exterior of mammalian cell cytoplasmic membranes. Earlier studies in rodent models indicate that Pig-a mutant red blood cells (RBCs) can be induced in animals treated with genotoxic agents, and that flow cytometry can be used to identify rare RBCs deficient in the GPI-anchored protein, CD59, as a marker of Pig-a gene mutation. We investigated if a similar approach could be used for detecting gene mutation in humans. We first determined the frequency of spontaneous CD59-deficient RBCs (presumed PIG-A mutants) in 97 self-identified healthy volunteers. For most subjects, the frequency of CD59-deficient RBCs was low (average of 5.1 ± 4.9 × 10(-6) ; median of 3.8 × 10(-6) and mutant frequency less than 8 × 10(-6) for 75% of subjects), with a statistically significant difference in median mutant frequencies between males and females. PIG-A RBC mutant frequency displayed poor correlation with the age and no correlation with the smoking status of the subjects. Also, two individuals had markedly increased CD59-deficient RBC frequencies of ~300 × 10(-6) and ~100 × 10(-6) . We then monitored PIG-A mutation in 10 newly diagnosed cancer patients undergoing chemotherapy with known genotoxic drugs. The frequency of CD59-deficient RBCs in the blood of the patients was measured before the start of chemotherapy and three times over a period of ~6 months while on/after chemotherapy. Responses were generally weak, most observations being less than the median mutant frequency for both males and females; the greatest response was an approximate three-fold increase in the frequency of CD59-deficient RBCs in one patient treated with a combination of cisplatin and etoposide. These results suggest that the RBC PIG-A assay can be adopted to measuring somatic cell mutation in humans. Further research is necessary to determine the assay's sensitivity in detecting mutations induced by genotoxic agents acting via different mechanisms. 相似文献
994.
995.
Totland GK Fjelldal PG Kryvi H Løkka G Wargelius A Sagstad A Hansen T Grotmol S 《Journal of anatomy》2011,219(4):490-501
This study addresses the effects of increased mechanical load on the vertebral bone of post-smolt Atlantic salmon by forcing them to swim at controlled speeds. The fish swam continuously in four circular tanks for 9 weeks, two groups at 0.47 body lengths (bl) × s(-1) (non-exercised group) and two groups at 2 bl × s(-1) (exercised group), which is just below the limit for maximum sustained swimming speed in this species. Qualitative data concerning the vertebral structure were obtained from histology and electron microscopy, and quantitative data were based on histomorphometry, high-resolution X-ray micro-computed tomography images and analysis of bone mineral content, while the mechanical properties were tested by compression. Our key findings are that the bone matrix secreted during sustained swimming had significantly higher mineral content and mechanical strength, while no effect was detected on bone in vivo architecture. mRNA levels for two mineralization-related genes bgp and alp were significantly upregulated in the exercised fish, indicating promotion of mineralization. The osteocyte density of the lamellar bone of the amphicoel was also significantly higher in the exercised than non-exercised fish, while the osteocyte density in the cancellous bone was similar in the two groups. The vertebral osteocytes did not form a functional syncytium, which shows that salmon vertebral bone responds to mechanical loading in the absence of an extensive connecting syncytial network of osteocytic cell processes as found in mammals, indicating the existence of a different mechanosensing mechanism. The adaptive response to increased load is thus probably mediated by osteoblasts or bone lining cells, a system in which signal detection and response may be co-located. This study offers new insight into the teleost bone biology, and may have implications for maintaining acceptable welfare for farmed salmon. 相似文献
996.
Magdi Shehata Sunil Bhandari Gopalakrishnan Venkat-Raman Richard Moore Richard D'Souza Hany Riad Ali Bakran Richard Baker Christine Needham Christopher Andrews 《Transplant international》2009,22(8):821-830
Despite the potential tolerability advantage of enteric-coated mycophenolate sodium (EC-MPS), no prospective, randomized trial has evaluated whether conversion from mycophenolate mofetil (MMF) to EC-MPS permits mycophenolic acid dose to be increased or gastrointestinal side-effects to be ameliorated. In a randomized, multicenter, open-label trial, kidney transplant recipients experiencing gastrointestinal side-effects either remained on MMF or switched to an equimolar dose of EC-MPS, adjusted 2 weeks subsequently to target the highest tolerated dose up to 1440 mg/day (EC-MPS) or 2000 mg/day (MMF). Patients were followed up to 12 weeks postrandomization. One hundred and thirty-four patients were randomized. The primary efficacy endpoint, the proportion of patients receiving a higher mycophenolic acid (MPA) dose at week 12 than at randomization, was significantly greater in the EC-MPS arm (32/68, 47.1%) than the MMF arm (10/61, 16.4%; P < 0.001). At the final visit, 50.0% (34/68) of EC-MPS patients were receiving the maximum recommended dose versus 26.2% (16/61) of MMF patients ( P = 0.007). Kidney transplant patients receiving reduced-dose MMF because of gastrointestinal side-effects can tolerate a significant increase in MPA dose after conversion to EC-MPS. Patient-reported gastrointestinal outcomes with higher doses of EC-MPS remained at least as good as in MMF-treated controls. 相似文献
997.
998.
Juan YS Chuang SM Kogan BA Mannikarottu A Huang CH Leggett RE Schuler C Levin RM 《International urology and nephrology》2009,41(3):513-521
Ischemia, reperfusion, and subsequent free radical damage have been implicated in many voiding disorders. Our goal was to
investigate further the mechanisms of these disorders, with particular emphasis on nerve and mitochondrial function and on
detrusor smooth-muscle cells. The effects on contractile responses to various stimulations, citrate synthase, choline acetyltransferase
activities, and vesicular acetylcholine transporter were evaluated after ischemia alone and ischemia/reperfusion 2 h, 7 days,
and 14 days. Nerve density and detrusor cell apoptosis were also measured. The contractile responses were significantly decreased
at both 7 and 14 days reperfusion, although at 14 days some recovery was observed. Similar patterns were seen for the intramural
nerves, both nerve cell cytoskeletal structures and cholinergic neurotransmitters. Citrate synthase activity was also depressed
by ischemia and 2 h reperfusion, but the activity recovered by 7 days. Detrusor cell apoptosis was not significantly affected
by ischemia and 2 h reperfusion; but showed an approximately 14-fold increase at both 7 and 14 days reperfusion. Reperfusion
following ischemia resulted in worsening intramural bladder nerve dysfunction, nerve fiber injury, mitochondrial injury, and
damaged detrusor muscle cells. However, at 14 days reperfusion, nerve and mitochondrial regeneration occurred and resulted
in partial recovery of contractile function. 相似文献
999.
Nicholas V. Cozzi Anupama Gopalakrishnan Lyndsey L. Anderson Joel T. Feih Alexander T. Shulgin Paul F. Daley Arnold E. Ruoho 《Journal of neural transmission (Vienna, Austria : 1996)》2009,116(12):1591-1599
N,N-dimethyltryptamine (DMT) is a potent plant hallucinogen that has also been found in human tissues. When ingested, DMT and
related N,N-dialkyltryptamines produce an intense hallucinogenic state. Behavioral effects are mediated through various neurochemical
mechanisms including activity at sigma-1 and serotonin receptors, modification of monoamine uptake and release, and competition
for metabolic enzymes. To further clarify the pharmacology of hallucinogenic tryptamines, we synthesized DMT, N-methyl-N-isopropyltryptamine (MIPT), N,N-dipropyltryptamine (DPT), and N,N-diisopropyltryptamine. We then tested the abilities of these N,N-dialkyltryptamines to inhibit [3H]5-HT uptake via the plasma membrane serotonin transporter (SERT) in human platelets and via the vesicle monoamine transporter
(VMAT2) in Sf9 cells expressing the rat VMAT2. The tryptamines were also tested as inhibitors of [3H]paroxetine binding to the SERT and [3H]dihydrotetrabenazine binding to VMAT2. Our results show that DMT, MIPT, DPT, and DIPT inhibit [3H]5-HT transport at the SERT with K
I
values of 4.00 ± 0.70, 8.88 ± 4.7, 0.594 ± 0.12, and 2.32 ± 0.46 μM, respectively. At VMAT2, the tryptamines inhibited [3H]5-HT transport with K
I
values of 93 ± 6.8, 20 ± 4.3, 19 ± 2.3, and 19 ± 3.1 μM, respectively. On the other hand, the tryptamines were very poor
inhibitors of [3H]paroxetine binding to SERT and of [3H]dihydrotetrabenazine binding to VMAT2, resulting in high binding-to-uptake ratios. High binding-to-uptake ratios support
the hypothesis that the tryptamines are transporter substrates, not uptake blockers, at both SERT and VMAT2, and also indicate
that there are separate substrate and inhibitor binding sites within these transporters. The transporters may allow the accumulation
of tryptamines within neurons to reach relatively high levels for sigma-1 receptor activation and to function as releasable
transmitters. 相似文献
1000.
Tibor Kovács Marianna Farsang Edina Vitaszil Péter Barsi Tamás Györke Imre Szirmai Anita Kamondi 《Journal of neural transmission (Vienna, Austria : 1996)》2009,116(12):1631-1634
Levetiracetam (LEV) has been shown to suppress myoclonus of various origins. Corticobasal degeneration (CBD), a progressive
neurodegenerative disorder with Parkinsonian syndrome, is frequently accompanied by myoclonus. We investigated the effect
of LEV on myoclonus in two CBD patients. LEV remarkably decreased the myoclonic activity in both patients already at 1,500 mg/day
dose. This is the first report on LEV alleviating myoclonus in CBD. Our data indicate that it might be worthwhile to assess
this effect in an appropriately designed study. 相似文献